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Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

Oncogene volume 26, pages 859–869 (2007)Cite this article

Abstract

Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-κB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-κB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-κB are essential for the autocrine growth and survival signaling of MK.

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Acknowledgements

We thank Dr L-M Wang (National Cancer Institute, Bethesda MD) for 32D and 32D/IRS-1 cell lines and Dr E Bowden (Georgetown University) for discussion and help with the experiments. This work is supported by grants from the National Cancer Institute, National Institutes of Health to AW CA101811 and by C06 RR14567 from the National Center for Research Resources, National Institutes of Health.

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  1. Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC, USA

    A H Kuo, G E Stoica, A T Riegel & A Wellstein

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  1. A H Kuo
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Correspondence to A Wellstein.

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Kuo, A., Stoica, G., Riegel, A. et al. Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene 26, 859–869 (2007). https://doi.org/10.1038/sj.onc.1209840

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